Targeted delivery of a drug should result in enhanced therapeutic efficacy with low to minimal side effects. This is a widely accepted concept, but limited in application due to lack of available technologies and process of validation. Biomedical nanotechnology can play an important role in this aspect. Biomedical nanotechnology is a burgeoning field and brings with it a myriad of opportunities and possibilities for advancing medical science and disease treatment. It is a multidisciplinary field cutting across the disciplines of biology, chemistry, materials science, engineering and medicine. At the nano scale, the physico-chemical, and biological properties of materials (metals, semiconductors, etc) differ fundamentally from their corresponding bulk counter part because of the quantum size effect e.g. gold nanoparticles (AuNPs) have wine red color whereas metallic gold is golden yellow and this wine red color can be tuned to either pink, or violet or blue by simply controlling the size and shape of AuNPs. Furthermore, nanoparticles also have large surface area to load multiple diagnostic (such as optical, radioisotope, magnetic) and therapeutic (such as drugs). In this application we want to exploit the unique properties of nanoparticles to create a targeted delivery system that will show better therapeutic efficacy with minimal to no side effects. The long-term goal of this project is to develop a nanoparticle-based delivery system for targeted delivery of cytotoxic drug with enhanced efficacy and reduced systemic toxicity. Our preliminary studies demonstrated that targeted delivery of a low dose of gemcitabine (Gem) as a gold nanoconjugate using anti-EGFR antibody (C225) as a targeting agent resulted in enhanced efficacy of the drug to inhibit the tumor growth in an orthotopic human xenograft model of pancreatic cancer. These results encouraged us to study, in depth, the nanofabrication process to improve the efficacy further and delineate the mechanism of enhanced drug activity. Therefore, our proposed studies center on gold nanoparticles (AuNPs) as a delivery vehicle, Gem as a cytotoxic drug and C225 as a targeting agent bound to the same gold core in a 2 in 1 fashion. The efficacy of nanofabrication will be tested in vitro first by determining the activity of the nanoconjugates against primary (PANC-1, MiaPaca2) and metastatic (AsPC-1) human pancreatic cancer cell lines. Therefore, studying efficacy in these models will allow us to determine the application of these systems in a wide range of disease condition (e.g. primary vs. metastatic disease, early stage vs. late stage of the disease). These cells also differ by EGFR expression pattern, cells with higher expression (PANC-1 and AsPC-1) will uptake more of the nanoconjugates than MiaPaca2 (with low EGFR expression). In vivo efficacy will then be tested in a preclinical mouse model of pancreatic cancer. The aims proposed in this study are designed to (i) optimize the nanofabrication process for targeted delivery in vitro and in vivo, (ii) to determine the pharmacokinetics, biodistribution and toxicity of the nanoconjugates in targeted vs. non-targeted delivery and (ii) to determine the therapeutic efficacy of the nanoconjugates to inhibit tumor growth, metastasis and increasing survival in targeted vs. non-targeted delivery. Pancreatic cancer is the 4th leading cause of cancer deaths in United States. Currently, surgery is the only option, however, due to late presentation only 10-15 % of the patients are amenable to surgery. The significance of this application is that it will study both targeted and non-targeted delivery of anti-cancer drugs using a nanodelivery system against pancreatic cancer where no effective therapy is currently available. Such a delivery in targeted fashion will enhance the efficacy of the drug with minimal side effects. According to our hypothesis, gemcitabine will have reduced systemic toxicity with better efficacy when delivered in a targeted fashion as a gold nanoconjugates. This application will also address a number of issues to obtain an optimized delivery vehicle such as loading of targeting agent and drug to a nanoparticle, bioavailability of the drug, biocompatibility and toxicity of gold nanoparticles and nanoconjugates. For those patients where the antibody is unsuccessful in targeting all the pancreatic tumor cells or patients that do not express EGFR, we may use other targets such as carcinoembryonic antigen (CEM) or carbohydrate antigen 19-9 (CA-19-9) or need to further identify other targeting molecules and expand our proof of concept experiments. Importantly, as we have already discussed that EGFR is overexpressed in a number of other cancers such as CRC, NHSC, NSCLC and gemcitabine is also used in other malignancies such as NSCLC, bladder, breast, therefore, this strategy could be used not only for the treatment of pancreatic cancers but also as a generalized approach in the treatment of a number of other malignancies such as CRC, NHLC, NSCLC, breast, ovarian, etc.

R01CA135011

2009-05-01

2015-02-28